Use of a combination of colchicine and a cxcr-2 inhibitors for the treatment or prevention of familial mediterranean fever (fmf) and flare-ups thereof

Abstract

The present invention relates to the treatment or prevention of Familial Mediterranean Fever (FMF) and flare-ups thereof comprising administering to the subject a combination of (i) colchicine, or a pharmaceutically acceptable salt thereof; and (ii) a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof. The preferred CXCR-2 inhibitor N-(6-(((2R,3S)-3,4-dihydroxy butan-2-yl)oxy)-2-((4-fluorobenzyl)thio)pyrimidin-4-yl)-3-methylazetidine-1-sulfonamide.

What is claimed is: 
     
         1 . A method for treating Familial Mediterranean Fever (FMF) in a subject in need thereof, comprising administering to the subject a combination of:
 (i) Colchicine, or a pharmaceutically acceptable salt thereof, and   (ii) a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof.   
     
     
         2 . A method for preventing Familial Mediterranean Fever (FMF) flare-ups in a subject having been diagnosed with FMF, comprising administering to the subject a combination of:
 (i) Colchicine, or a pharmaceutically acceptable salt thereof, and   (ii) a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof.   
     
     
         3 . A method for treating acute Familial Mediterranean Fever (FMF) flare-ups in a subject having been diagnosed with FMF, comprising administering to the subject a combination of:
 (i) Colchicine, or a pharmaceutically acceptable salt thereof; and   (ii) a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof.   
     
     
         4 . A method for decreasing the severity of Familial Mediterranean Fever (FMF) flare-ups in a subject having been diagnosed with FMF, comprising administering to the subject a combination of:
 (i) Colchicine, or a pharmaceutically acceptable salt thereof, and   (ii) a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof.   
     
     
         5 . The method of  claim 4 , wherein the severity of the FMF flare-ups is decreased as compared to a subject being administered Colchicine alone. 
     
     
         6 . The method of  claim 4 , wherein the severity of the FMF flare-ups is decreased as compared to a subject receiving no therapy. 
     
     
         7 . The method of  claim 5  or  6 , wherein the severity of the flare-ups is decreased by at least about 50%. 
     
     
         8 . The method of  claim 5  or  6 , wherein the severity of the flare-ups is decreased by at least about 70%. 
     
     
         9 . The method of  claim 5  or  6 , wherein the severity of the flare-ups is decreased by at least about 90%. 
     
     
         10 . The method of  claim 5  or  6 , wherein the severity of the flare-ups is decreased by at least about 99%. 
     
     
         11 . A method for decreasing the occurrence of Familial Mediterranean Fever (FMF) flare-ups in a subject having been diagnosed with FMF, comprising administering to the subject a combination of:
 (i) Colchicine, or a pharmaceutically acceptable salt thereof, and   (ii) a CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof.   
     
     
         12 . The method of  claim 11 , wherein the occurrence of the FMF flare-ups is decreased as compared to a subject being administered Colchicine alone. 
     
     
         13 . The method of  claim 11 , wherein the occurrence of the FMF flare-ups is decreased as compared to a subject receiving no therapy. 
     
     
         14 . The method of  claim 12  or  13 , wherein the occurrence of the flare-ups is decreased by at least about 50%. 
     
     
         15 . The method of  claim 12  or  13 , wherein the occurrence of the flare-ups is decreased by at least about 70%. 
     
     
         16 . The method of  claim 12  or  13 , wherein the occurrence of the flare-ups is decreased by at least about 90%. 
     
     
         17 . The method of  claim 12  or  13 , wherein the occurrence of the flare-ups is decreased by at least about 99%. 
     
     
         18 . The method of any one of  claim 1 - 17 , wherein the combination is a synergistic combination. 
     
     
         19 . The method of any one of  claim 1 - 18 , wherein the CXCR-2 inhibitor is N-(6-(((2R,3S)-3,4-dihydroxy butan-2-yl)oxy)-2-((4-fluoro benzyl)thio)pyrimidin-4-yl)-3-methylazetidine-1-sulfonamide: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         20 . The method of any one of  claims 1 - 19 , wherein the subject is colchicine-resistant. 
     
     
         21 . The method of  claim 20 , wherein colchicine-resistant means the subject has stopped responding to Colchicine treatment. 
     
     
         22 . The method of  claim 20 , wherein colchicine-resistant means more than 1 flare-up every 3 months despite treatment with 2 mg/day of colchicine. 
     
     
         23 . The method of  claim 20 , wherein colchicine-resistant means one flare-up or more per month in a subject who is receiving the maximally Colchicine tolerated dose for six months or more. 
     
     
         24 . The method of  claim 20 , wherein colchicine-resistant means more than 6 flare-ups per year. 
     
     
         25 . The method of  claim 20 , wherein colchicine-resistant means more than 3 flare-ups over 4-6 months. 
     
     
         26 . The method of any one of  claims 2 - 25 , wherein the FMF flare-ups comprise fever, abdominal pain, joint pain, pleuritis, pericarditis, or any combinations thereof. 
     
     
         27 . The method of any one of  claims 2 - 26 , wherein the FMF flare-ups comprise fever. 
     
     
         28 . The method of any one of  claims 2 - 26 , wherein the FMF flare-ups comprise abdominal pain. 
     
     
         29 . The method of any one of  claims 2 - 26 , wherein the FMF flare-ups comprise joint pain. 
     
     
         30 . The method of any one of  claims 1 - 29 , wherein colchicine is administered in a therapeutically effective amount. 
     
     
         31 . The method of any one of  claims 1 - 29 , wherein colchicine is administered in a sub-therapeutically effective amount. 
     
     
         32 . The method of  claim 31 , wherein the sub-therapeutic amount of colchicine results in fewer side effects than a therapeutic amount of colchicine. 
     
     
         33 . The method of  claim 30  or  31 , wherein the amount of Colchicine, or a pharmaceutically acceptable salt thereof, is between about 0.3 mg/day and about 3.0 mg/day. 
     
     
         34 . The method of  claim 30  or  31 , wherein the amount of Colchicine, or a pharmaceutically acceptable salt thereof, is between about 0.6 mg/day and about 2.4 mg/day. 
     
     
         35 . The method of  claim 30  or  31 , wherein the amount of Colchicine, or a pharmaceutically acceptable salt thereof, is between about 1.2 mg/day and about 2.4 mg/day. 
     
     
         36 . The method of  claim 30  or  31 , wherein the amount of Colchicine, or a pharmaceutically acceptable salt thereof, is about 0.6 mg/day. 
     
     
         37 . The method of  claim 30  or  31 , wherein the amount of Colchicine, or a pharmaceutically acceptable salt thereof, is about 1.2 mg/day. 
     
     
         38 . The method of  claim 30  or  31 , wherein the amount of Colchicine, or a pharmaceutically acceptable salt thereof, is about 2.4 mg/day. 
     
     
         39 . The method of  claim 30  or  31 , wherein the amount of Colchicine, or a pharmaceutically acceptable salt thereof, is about 0.5 mg/day. 
     
     
         40 . The method of  claim 30  or  31 , wherein the amount of Colchicine, or a pharmaceutically acceptable salt thereof, is about 1.0 mg/day. 
     
     
         41 . The method of  claim 30  or  31 , wherein the amount of Colchicine, or a pharmaceutically acceptable salt thereof, is about 1.5 mg/day. 
     
     
         42 . The method of  claim 30  or  31 , wherein the amount of Colchicine, or a pharmaceutically acceptable salt thereof, is about 2.0 mg/day. 
     
     
         43 . The method of  claim 30  or  31 , wherein the amount of Colchicine, or a pharmaceutically acceptable salt thereof, is about 2.5 mg/day. 
     
     
         44 . The method of  claim 30  or  31 , wherein the amount of Colchicine, or a pharmaceutically acceptable salt thereof, is about 3.0 mg/day. 
     
     
         45 . The method of any one of  claims 1 - 44 , wherein the CXCR-2 inhibitor is administered in a therapeutically effective amount. 
     
     
         46 . The method of any one of  claims 1 - 44 , wherein the CXCR-2 inhibitor is administered in a sub-therapeutically effective amount. 
     
     
         47 . The method of  claim 45  or  46 , wherein the amount of the CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, is between about 10 mg/day and about 500 mg/day. 
     
     
         48 . The method of  claim 47 , wherein the amount of the CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, is about 200 mg/day. 
     
     
         49 . The method of  claim 47 , wherein the amount of the CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, is about 300 mg/day. 
     
     
         50 . The method of  claim 47 , wherein the amount of the CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, is about 400 mg/day. 
     
     
         51 . The method of any one of  claims 1 - 50 , wherein the CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, and Colchicine, or a pharmaceutically acceptable salt thereof are formulated in the same pharmaceutical composition. 
     
     
         52 . The method of  claim 51 , wherein the pharmaceutical composition is a solution, suspension, tablet, or capsule. 
     
     
         53 . The method of  claim 52 , wherein the pharmaceutical composition is formulated as a sustained release or delayed release formulation. 
     
     
         54 . The method of any one of  claims 1 - 50 , wherein the CXCR-2 inhibitor, or a pharmaceutically acceptable salt thereof, and Colchicine, or a pharmaceutically acceptable salt thereof are formulated in different pharmaceutical compositions. 
     
     
         55 . The method of  claim 54 , wherein the Colchicine pharmaceutical composition is a solution, suspension, tablet, or capsule. 
     
     
         56 . The method of  claim 54 , wherein the Colchicine pharmaceutical composition is formulated as a sustained release or delayed release formulation. 
     
     
         57 . The method of  claim 54 , wherein the CXCR-2 inhibitor pharmaceutical composition is a solution, suspension, tablet, or capsule. 
     
     
         58 . The method of  claim 54 , wherein the CXCR-2 inhibitor pharmaceutical composition is formulated as a sustained release or delayed release formulation. 
     
     
         59 . The method of any one of  claims 1 - 50 , wherein the CXCR-2 inhibitor and Colchicine are administered concomitantly. 
     
     
         60 . The method of any one of  claims 1 - 50 , wherein the CXCR-2 inhibitor and Colchicine are administered sequentially. 
     
     
         61 . The method of any one of  claims 2 - 60 , wherein the FMF flare-up is an acute FMF flare-up. 
     
     
         62 . The method of any one of  claims 2 - 61 , wherein the subject presents with a C-reactive protein (CRP) level of greater than 10 mg/L.